Brysa Alvarado, Graduate Student, Meisel Lab, GW Department of Chemistry

The Department of Chemistry Presents:  Brysa Alvarado, Graduate Student, Meisel Lab, GW Department of Chemistry

The use of small molecules to target deep hydrophobic pockets in disease-associated proteins is a well-known strategy in drug discovery. However, there remains an undruggable portion of the human proteome that these therapeutics fail to target. Many of these proteins lack targetable pockets and engage in protein-protein interactions (PPIs) that occur over a large flat surface area. Foldamers are a class of oligomeric structures that fold into well-defined conformations in solution and can be designed to mimic protein surfaces and disrupt PPIs. However, there remains a need to develop structural elements that better control foldamer conformational preference in solution. In this work, we synthesize regioisomeric aromatic oligoamide foldamers and investigate how the substitution pattern around the amide bond influences the conformation and hydrogen bonding in solution. Variable temperature, one-dimensional and two-dimensional nuclear magnetic resonance (NMR) techniques were used to study the relative conformation and H-bonding in solution, while single crystal x-ray diffraction was used to observe the solid-state structure and dimer topography. Preliminary data suggest that the major conformational determinants of these oligomers are primarily driven by the substitution pattern around the arylamide. We therefore hypothesize that the conformation of longer oligomers and macrocycles can be controlled by tuning the geometry that links adjacent monomers. In conclusion, foldamers have potential to be valuable tools to target PPIs and having precise control of the conformation will help achieve the selectivity and affinity that’s necessary for targeting these interactions.

BIO

Brysa graduated from California State University San Marcos (CSUSM) in 2020 with a B.S. in Biochemistry. While at CSUSM, she worked as an undergraduate researcher in the lab Dr. Robert Iafe studying substitution reactions catalyzed by gold(I). In the summer of 2020, she moved to DC to join the Chemistry Department at GW, and joined Dr. Joe Meisel’s lab. Since joining the Meisel lab, her research has focused on synthesizing peptidomimetic scaffolds and studying their hydrogen bonding & conformation.

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